Investigating the effects of 25-hydroxyvitamin D3 on clinical outcomes in multiple sclerosis patients: A randomized, double-blind clinical trial- a pilot study.

BACKGROUND: The primary objective of this clinical trial was to assess whether administrating oral calcifediol (25(OH)D3) could enhance the clinical outcomes of patients diagnosed with multiple sclerosis. METHODS: This clinical trial was designed as a randomized, double-blind, two-arm study, with 25 participants receiving daily 50 µg of calcifediol and 25 people receiving daily 50 µg of cholecalciferol. The primary outcomes were serum levels of 25(OH)D3, number of relapses, changes in Kurtzke Expanded Disability Status Scale (EDSS), the 25-foot walk, and cognitive function. RESULTS: At the end of the trial, delta serum concentrations of 25(OH)D3 were 85.32±40.94 ng/ml in the calcifediol group compared to 13.72±11.56 ng/ml in the cholecalciferol group; 84 % of the calcifediol group and none of the cholecalciferol group had circulating 25(OH)D3 concentrations exceeding 70 ng/ml. While both groups showed an overall trend towards improved cognitive function at the end of the study, the calcifediol group exhibited greater improvements in most cognitive tests. However, the trial had no significant beneficial effects on MS relapse, EDSS score, quality of life, or fatigue in either group, the calcifediol or cholecalciferol. CONCLUSIONS: The trial shows that calcifediol is more effective in rapidly increasing 25(OH)D3 levels in MS patients compared to cholecalciferol when administrated at a similar dosage.

Utilizing psoas muscle cross-sectional area to predict functional outcome.

Background: This study evaluated psoas muscle area (PMA) as a predictor of frailty and functional outcome in trauma patients. Methods: The cohort included 211 trauma patients admitted to an urban level I trauma center from March 2012 to May 2014 who consented to participate in a longitudinal study and underwent abdominal-pelvic computed tomography scans during their initial evaluation. Physical component scores (PCS) of the Veterans RAND 12-Item Health Survey were administered to assess physical functionality at baseline and at 3, 6, and 12 months after injury. PMA in mm2 and Hounsfield units was calculated using the Centricity PACS system. Statistical models were stratified by injury severity score (ISS), <15 or ≥15, and adjusted for age, sex, and baseline PCS. Follow-up PCS were analyzed using general linear regression models. Results: For participants with an ISS <15, increased PMA was significantly associated with higher PCS at 3 (P = 0.008), 6 (P = 0.02), and 12 months (P = 0.002), although this relationship was not statistically significant for ISS ≥15 (P = 0.85, 0.66, 0.61). Conclusion: For mild to moderately injured (but not seriously injured) patients, those with larger psoas muscles experience better functional outcomes after injury.

Hereditary Metabolic Bone Diseases: A Review of Pathogenesis, Diagnosis and Management.

Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases. In this review, we examine 25 selected hereditary metabolic bone diseases and recognized genetic variations of 78 genes that represent each of the three groups, including sclerosing bone disorders, disorders of defective bone mineralization and disorder of bone matrix and cartilage formation. We also review pathophysiology, manifestation and treatment for each disease. Advances in molecular genetics and basic sciences has led to accurate genetic diagnosis and novel effective therapeutic strategies for some diseases. For other diseases, the genetic basis and pathophysiology remain unclear. Further researches are therefore crucial to innovate ways to overcome diagnostic challenges and develop effective treatment options for these orphan diseases.

Alterations in circulating levels of vitamin D binding protein, total and bioavailability of vitamin D in diabetic retinopathy patients.

AIMS: This study aimed to investigate the association between circulating levels of vitamin D binding protein (VDBP) and its genotypes and diabetic retinopathy risk. METHODS: This case-control study recruited 154 patients with type 2 diabetes mellitus; 62 with diabetic retinopathy (DR) and 92 without DR and diabetic nephropathy (DN). Circulating levels of 25-hydroxyvitamin D3 and VDBP levels were measured in the patients. The genotype and phenotype of VDBP were evaluated based on two common VDBP variations; rs7041 and rs4588. RESULTS: Serum levels of VDBP were significantly lower in patients with DR than in patients without DR and/or DN (Ln-VDBP (µg/ml): 6.14 ± 0.92 vs. 6.73 ± 1.45, p = 0.001) even after adjustment for age, sex, body mass index, disease duration, estimated glomerular filtration rate (eGFR), HbA1C, insulin therapy profile, and serum levels of 25(OH)D. The distribution of VDBP phenotypes and genotypes in the two studied groups were nearly the same, and the distribution was similar to that of the general population. CONCLUSIONS: In this study, we found the association between lower circulating levels of VDBP and risk of DR. However, the precise mechanism linking these two remains unknown. Further and more in-depth research is needed to find out the underlying causes of the relationship.

Treatment With 25-Hydroxyvitamin D3 (Calcifediol) Is Associated With a Reduction in the Blood Neutrophil-to-Lymphocyte Ratio Marker of Disease Severity in Hospitalized Patients With COVID-19: A Pilot Multicenter, Randomized, Placebo-Controlled, Double-Blinded Clinical Trial.

OBJECTIVE: The goal of this randomized, double-blinded, placebo-controlled clinical trial was to investigate the therapeutic efficacy of oral 25-hydroxyvitamin D3 (25(OH)D3) in improving vitamin D status in vitamin D-deficient/vitamin D-insufficient patients infected with the SARS-CoV-2 (COVID-19) virus. METHODS: This is a multicenter, randomized, double-blinded, placebo-controlled clinical trial. Participants were recruited from 3 hospitals that are affiliated to [Institution Blinded for Review] and [Institution Blinded for Review]. RESULTS: A total 106 hospitalized patients who had a circulating 25(OH)D3 concentration of <30 ng/mL were enrolled in this study. Within 30 and 60 days, 76.4% (26 of 34) and 100% (24 of 24) of the patients who received 25(OH)D3 had a sufficient circulating 25(OH)D3 concentration, whereas ≤12.5% of the patients in the placebo group had a sufficient circulating 25(OH)D3 concentration during the 2-month follow-up. We observed an overall lower trend for hospitalization, intensive care unit duration, need for ventilator assistance, and mortality in the 25(OH)D3 group compared with that in the placebo group, but differences were not statistically significant. Treatment with oral 25(OH)D3 was associated with a significant increase in the lymphocyte percentage and decrease in the neutrophil-to-lymphocyte ratio in the patients. The lower neutrophil-to-lymphocyte ratio was significantly associated with reduced intensive care unit admission days and mortality. CONCLUSION: Our analysis indicated that oral 25(OH)D3 was able to correct vitamin D deficiency/insufficiency in patients with COVID-19 that resulted in improved immune function by increasing blood lymphocyte percentage. Randomized controlled trials with a larger sample size and higher dose of 25(OH)D3 may be needed to confirm the potential effect of 25(OH)D3 on reducing clinical outcomes in patients with COVID-19.

Fetal Fractures in an Infant with Maternal Ehlers-Danlos Syndrome, CCDC134 Pathogenic Mutation and a Negative Genetic Test for Osteogenesis Imperfecta.

Intrauterine fractures are a rare clinical finding caused by abnormal early-life osteogenesis. In this case report, we reported a male infant with twenty-three intrauterine/fetal fractures resembling osteogenesis imperfecta and tested negative for COL1A1 and COL1A2 mutations. The infant's mother had Ehlers-Danlos syndrome, hypermobility type. Whole-genome sequencing revealed that there were no pathologic mutations previously documented to be associated with intrauterine fracture. Genetic mutations reported to be associated with fragility fractures were identified. These include the pathogenic homozygous mutation in the CCDC134 gene. Other genetic variants that might be responsible for variable expressivity of the skeletal manifestation include the homozygous variants of the genes CCDC134, COL15A1 and ZFPM1, and the heterozygous variants of the genes MYH3, BCHE, AUTS2. This is the first reported case of in utero fractures, that was confirmed by X-ray after birth, in an infant who had no genetic evidence for osteogenesis imperfecta, had a homozygous pathogenic mutation of an osteogenesis gene and whose mother had Ehlers-Danlos syndrome hypermobility type. Therefore, we have identified a new genetic cause for in utero fractures. If after birth, this infant were found to have these fractures in various stages of healing with a negative genetic test for osteogenesis imperfecta he would have been misdiagnosed as due to nonaccidental trauma.

A pilot-randomized, double-blind crossover trial to evaluate the pharmacokinetics of orally administered 25-hydroxyvitamin D3 and vitamin D3 in healthy adults with differing BMI and in adults with intestinal malabsorption.

BACKGROUND: Obese and malabsorptive patients have difficulty increasing serum 25-hydroxyvitamin D [25(OH)D] after taking vitamin D supplementation. Since 25(OH)D is more hydrophilic than vitamin D, we hypothesized that oral 25(OH)D supplementation is more effective in increasing serum 25(OH)D concentrations in these patients. OBJECTIVES: We aimed to investigate the pharmacokinetics of oral 25-hydroxyvitamin D3 [25(OH)D3] and oral vitamin D3 in healthy participants with differing BMI and malabsorptive patients. METHODS: A randomized, double-blind crossover trial was performed in 6 malabsorptive patients and 10 healthy participants who were given 900 µg of either vitamin D3 or 25(OH)D3 orally followed by a pharmacokinetic study (PKS). After ≥28 d from the first dosing, each participant returned to receive the other form of vitamin D and undergo another PKS. For each PKS, serum vitamin D3 and 25(OH)D3 were measured at baseline and at 2, 4, 6, 8, and 12 h and days 1, 2, 3, 7, and 14. Pharmacokinetic parameters were calculated. RESULTS: Data were expressed as means ± SEMs. The PKS of 900 µg vitamin D3 revealed that malabsorptive patients had 64% lower AUC than healthy participants (1177 ± 425 vs. 3258 ± 496 ng · h/mL; P < 0.05). AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.540). The 10 healthy participants were ranked by BMI and categorized into higher/lower BMI groups (5/group). The PKS of 900 µg vitamin D3 showed that the higher BMI group had 53% lower AUC than the lower BMI group (2089 ± 490 vs. 4427 ± 313 ng · h/mL; P < 0.05), whereas AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.500). CONCLUSIONS: Oral 25(OH)D3 may be a good choice for managing vitamin D deficiency in malabsorption and obesity. This trial was registered at clinicaltrials.gov as (NCT03401541.

Vitamin D and Its Potential Benefit for the COVID-19 Pandemic.

Vitamin D is known not only for its importance for bone health but also for its biologic activities on many other organ systems. This is due to the presence of the vitamin D receptor in various types of cells and tissues, including the skin, skeletal muscle, adipose tissue, endocrine pancreas, immune cells, and blood vessels. Experimental studies have shown that vitamin D exerts several actions that are thought to be protective against coronavirus disease (COVID-19) infectivity and severity. These include the immunomodulatory effects on the innate and adaptive immune systems, the regulatory effects on the renin-angiotensin-aldosterone-system in the kidneys and the lungs, and the protective effects against endothelial dysfunction and thrombosis. Prior to the COVID-19 pandemic, studies have shown that vitamin D supplementation is beneficial in protecting against risk of acquiring acute respiratory viral infection and may improve outcomes in sepsis and critically ill patients. There are a growing number of data connecting COVID-19 infectivity and severity with vitamin D status, suggesting a potential benefit of vitamin D supplementation for primary prevention or as an adjunctive treatment of COVID-19. Although the results from most ongoing randomized clinical trials aiming to prove the benefit of vitamin D supplementation for these purposes are still pending, there is no downside to increasing vitamin D intake and having sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at a level of least 30 ng/mL (75 nmol/L) and preferably 40 to 60 ng/mL (100-150 nmol/L) to minimize the risk of COVID-19 infection and its severity.

Association of Vitamin D Status With Hospital Morbidity and Mortality in Adult Hospitalized Patients With COVID-19.

OBJECTIVE: To determine the association between vitamin D status and morbidity and mortality in adult hospitalized coronavirus disease 2019 (COVID-19) patients METHODS: We performed a retrospective chart review study in COVID-19 patients aged ≥18 year hospitalized at Boston University Medical Center between March 1 and August 4, 2020. All studied patients tested positive for COVID-19 and had serum levels of 25-hydroxyvitamin D (25[OH]D) results measured within 1 year prior to the date of positive tests. Medical information was retrieved from the electronic medical record and was analyzed to determine the association between vitamin D status and hospital morbidity and mortality. RESULTS: Among the 287 patients, 100 (36%) were vitamin D sufficient (25[OH]D >30 ng/mL) and 41 (14%) died during hospitalization. Multivariate analysis in patients aged ≥65 years revealed that vitamin D sufficiency (25[OH]D ≥30 ng/mL) was statistically significantly associated with decreased odds of death (adjusted OR 0.33, 95% CI, 0.12-0.94), acute respiratory distress syndrome (adjusted OR 0.22, 95% CI, 0.05-0.96), and severe sepsis/septic shock (adjusted OR 0.26, 95% CI, 0.08-0.88), after adjustment for potential confounders. Among patients with body mass index <30 kg/m2, vitamin D sufficiency was statistically significantly associated with a decreased odds of death (adjusted OR 0.18, 95% CI, 0.04-0.84). No significant association was found in the subgroups of patients aged <65 years or with body mass index ≥30 kg/m2. CONCLUSION: We revealed an independent association between vitamin D sufficiency defined by serum 25(OH)D ≥30 ng/mL and decreased risk of mortality from COVID-19 in elderly patients and patients without obesity.

Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection.

BACKGROUND: To investigate the association between serum 25-hydroxyvitamin D levels and its effect on adverse clinical outcomes, and parameters of immune function and mortality due to a SARS-CoV-2 infection. STUDY DESIGN: The hospital data of 235 patients infected with COVID-19 were analyzed. RESULTS: Based on CDC criteria, among our study patients, 74% had severe COVID-19 infection and 32.8% were vitamin D sufficient. After adjusting for confounding factors, there was a significant association between vitamin D sufficiency and reduction in clinical severity, inpatient mortality serum levels of C-reactive protein (CRP) and an increase in lymphocyte percentage. Only 9.7% of patients older than 40 years who were vitamin D sufficient succumbed to the infection compared to 20% who had a circulating level of 25(OH)D< 30 ng/ml. The significant reduction in serum CRP, an inflammatory marker, along with increased lymphocytes percentage suggest that vitamin D sufficiency also may help modulate the immune response possibly by reducing risk for cytokine storm in response to this viral infection. CONCLUSION: Therefore, it is recommended that improving vitamin D status in the general population and in particular hospitalized patients has a potential benefit in reducing the severity of morbidities and mortality associated with acquiring COVID-19.

The predictive role of circulating telomerase and vitamin D for long-term survival in patients undergoing coronary artery bypass grafting surgery (CABG).

BACKGROUNDS: Cardiovascular disease (CVD) is the leading cause of mortality all over the globe. Inflammation is believed to play a pivotal role in the pathophysiology of CVD. While there are studies on the interrelationship of telomerase and vitamin D and their involvement in CVD, their independent contributions to long-term outcomes in patients with CVD are not well-defined. This study aimed to investigate the association of both telomerase and vitamin D concentrations with 10-year survival among candidates of coronary artery bypass grafting (CABG) surgery. METHODS: Participants were 404 patients from Tehran Heart Center-Coronary Outcome Measurement (THC-COM) cohort who were recruited from CABG surgery candidates in 2006. In addition to demographic and clinical data including risk factors for coronary artery disease, laboratory parameters such as markers of inflammation as well as baseline serum 25-hydroxy vitamin D [25(OH)D] and telomerase concentrations were measured. Cardiac function indexes alongside outcome measures such as mortality and survival days were recorded for every patient up to 10 years after CABG. Cox-proportional hazard model was used to study the association between all-cause mortality and research parameters. RESULTS: The mean serum telomerase enzyme level was 24.92 ±21.4 nmol/L and the mean serum 25(OH)D was 27.27±10.3 ng/mL. 10-year mortality was reported in 64 (15.8%) patients. 25(OH)D was categorized into three groups (<20, 20-30, and >30) and the cut-point for telomerase was set at 25.0 nmol/L. In Cox regression analysis, higher levels of telomerase (>25 nmol/L) were significantly associated with longer survival (p = 0.041), whereas 25(OH)D concentrations were not associated with survival time. Further analysis showed that telomerase concentrations significantly predicted survival only in the presence of insufficient levels of 25(OH)D (20-30 ng/mL) (p = 0.037). CONCLUSIONS: Telomerase can be regarded as a potential predictor of long-term outcomes in patients who underwent CABG. However, the association of telomerase with the mortality may be modified by vitamin D concentrations.

Evaluation of a Ultraviolet B Light Emitting Diode (LED) for Producing Vitamin D3 in Human Skin.

AIM: A commercially available light emitting diode (LED) that transmitted narrow band ultraviolet B (UVB) radiation was evaluated for its efficacy and efficiency to produce vitamin D3 in human skin. MATERIALS AND METHODS: Human skin samples were obtained from surgical procedures. The LED had peak emission wavelength of 295 nm. Skin samples were exposed to the UVB-LED for varying times and then were analyzed by high-pressure liquid chromatography (HPLC) to determine the vitamin D3 content. RESULTS: There was a statistically significant time- and dose-dependent increase in the percent of 7-dehydrocholesterol that was converted to vitamin D3 in the skin type II samples; 1.3%±0.5, 2.3%±0.6 and 4.5%±1.67 after exposure to 0.75 (11.7 mJ/cm2), 1.5 (23.4 mJ/cm2) and 3 (46.8 mJ/cm2) minimal erythemal doses (MEDs), respectively. CONCLUSION: The UVB-LED was effective and efficient in generating vitamin D3 in human skin, in vitro. The amount of vitamin D3 production increased in a dose-dependent fashion with increased UVB energy. UVB-LEDs can be developed for devices that can efficiently produce vitamin D3 in human skin.

The Effect of Various Doses of Oral Vitamin D3 Supplementation on Gut Microbiota in Healthy Adults: A Randomized, Double-blinded, Dose-response Study.

BACKGROUND/AIM: To investigate the effects of vitamin D3 supplementation on gut microbiota. PATIENTS AND METHODS: Twenty adults with vitamin D insufficiency/deficiency [25(OH)D <30 ng/ml] were enrolled and given 600, 4,000 or 10,000 IUs/day of oral vitamin D3 Stool samples were collected at baseline and 8 weeks for identifying gut microbiota using 16S rRNA gene amplification and sequencing. RESULTS: Baseline serum 25(OH)D was associated with increased relative abundance of Akkermansia and decreased relative abundance of Porphyromonas (p<0.05). After the intervention, we observed a dose-dependent increase in relative abundance of Bacteroides with a significant difference between the 600 IUs and the 10,000 IUs groups (p=0.027), and Parabacteroides with a significant difference between the 600 IUs and the 4,000 IUs groups (p=0.039). CONCLUSION: Increased serum 25(OH)D was associated with increased beneficial bacteria and decreased pathogenic bacteria. A dose-dependent increase in bacteria associated with decreased inflammatory bowel disease activity was observed after vitamin D3 supplementation.

Evaluation of Effectiveness of Ultraviolet Emitting Lamps on the Cutaneous Production of Vitamin D3: Relationship of the Lamps Vitamin D3 Producing Potential to the Production of 8-Hydroxy-2'-Deoxyguanosine and Nitric Oxide.

BACKGROUND/AIM: To assess the effectiveness of three UV emitting lamps on the cutaneous production of vitamin D3, a marker of DNA damage and nitric oxide production in human skin. MATERIALS AND METHODS: Human skin samples (skin types II, III and IV) obtained from surgery were exposed to three different UV emitting lamps for varying times and then extracted and chromatographed to determine the vitamin D3 content. The skin samples exposed to the 3 UV emitting lamps were also evaluated for 8-hydroxy-2'-deoxyguanosine (a marker of DNA damage) and nitric oxide production. RESULTS: It was observed that the spectral output of the 3 lamps had different effects on the cutaneous production of vitamin D3, 8-hydroxy-2'-deoxyguanosine and nitric oxide production. One lamp demonstrated optimal production of vitamin D3 with the least amount of DNA damage and intermediate production of nitric oxide suggesting that it could be developed into a device for treating vitamin D deficiency. CONCLUSION: The spectral output of the experimental UVB emitting lamps significantly influenced the cutaneous production of vitamin D3 8-hydroxy-2'-deoxyguanosine and nitric oxide.

Variable Genomic and Metabolomic Responses to Varying Doses of Vitamin D Supplementation.

BACKGROUND/AIM: To assess the impact of vitamin D supplementation on genomic and metabolomic profiles and relate them to the individual's responsiveness to varying doses of vitamin D3 Patients and Methods: Healthy adults were given either 600, 4000 or 10,000 IUs vitamin D3/day for 6 months. Circulating parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], calcium, peripheral white blood cells broad gene expression and urine and serum metabolomic profiles were evaluated. RESULTS: There was a dose-dependent effect of vitamin D supplementation on serum 25(OH)D, PTH and broad gene expression. Serum calcium levels remained normal for all study subjects and no untoward toxicity was observed. The metabolomic profiles were related to the genomic expression analysis. There were significant inter-individual effects on gene expression and metabolomic profile in response to the same dose of vitamin D3 supplementation, despite similar changes in 25(OH)D and PTH concentrations. CONCLUSION: These results may help explain the variability observed in clinical trials regarding vitamin D's non-calcemic health benefits.

Man of Steel Syndrome: Silicone and Mineral Oil Injections With Associated Hypercalcemia, Hypophosphatemia, and Proximal Muscle Weakness.

Silicone/mineral oil-induced granulomas have been described as an inflammatory granulomatous response when silicone/mineral oil is injected for cosmetic purposes. These sclerosing granulomas can lead to hypercalcemia. Here we present a 33-year-old man with hypercalcemia, hypophosphatemia, progressively worsening fatigue, severe proximal muscle weakness, and depression. He had an athletic build with increased muscle bulk and several areas of indurated, nontender, firm, well-circumscribed lesions in the subcutaneous tissue of his anterior pectoralis, triceps, and biceps bilaterally because of injecting himself with silicone/mineral oil-based product into his muscles. Sclerosing granulomas were diagnosed on the MRI. He had extremely low or undetectable serum levels of 25-hydroxyvitamin D [25(OH)D], and persistently elevated serum levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] and calcium. He developed hypophosphatemia associated with elevated levels of fibroblast growth factor 23 (FGF-23) and severe proximal muscle weakness. Treatment with systemic steroids, furosemide, calcitonin, ketoconazole, and denosumab resulted in a significant decrease in his serum calcium, but with minimal impact on his hypophosphatemia and fatigue.Correcting his severe vitamin D deficiency with small doses of vitamin D and raising his blood level of 25(OH)D from undetectable to 10 ng/mL without significantly affecting his serum calcium or phosphate was effective in reversing his severe proximal muscle weakness, permitting him to lift his head and to be free of his wheelchair. Although measurement of the 1,25(OH)2D level is not mandatory in all cases of hypercalcemia, it is indicated in a patient who has low serum PTH levels. Clinicians need to be aware that vitamin D deficiency can cause severe proximal muscle weakness such that the patient is unable to lift his head from his chest or ambulate. This may lead to a psychiatric disorder misdiagnosis. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Disassociation of Vitamin D's Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial.

The aims of this randomized controlled double-blind clinical trial were to assess the impact of vitamin D supplementation on calcium metabolism and non-calcemic broad gene expression by relating them to the individual's responsiveness to varying doses of vitamin D3. Thirty healthy adults were randomized to receive 600, 4,000 or 10,000 IU/d of vitamin D3 for 6 months. Circulating parathyroid hormone (PTH), 25(OH)D, calcium and peripheral white blood cells broad gene expression were evaluated. We observed a dose-dependent increase in 25(OH)D concentrations, decreased PTH and no change in serum calcium. A plateau in PTH levels was achieved at 16 weeks in the 4000 and 10,000 IU/d groups. There was a dose-dependent 25(OH)D alteration in broad gene expression with 162, 320 and 1289 genes up- or down-regulated in their white blood cells, respectively. Our results clearly indicated that there is an individual's responsiveness on broad gene expression to varying doses of vitamin D3. Vitamin D3 supplementation at 10,000 IU/d produced genomic alterations several fold higher than 4,000 IU/d even without further changes in PTH levels. Our findings may help explain why there are some inconsistency in the results of different vitamin D's clinical trials.

Vitamin D for skeletal and non-skeletal health: What we should know.

Vitamin D plays an essential role in regulating calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. Humans obtain vitamin D from sunlight exposure, dietary foods and supplements. There are two forms of vitamin D: vitamin D3 and vitamin D2. Vitamin D3 is synthesized endogenously in the skin and found naturally in oily fish and cod liver oil. Vitamin D2 is synthesized from ergosterol and found in yeast and mushrooms. Once vitamin D enters the circulation it is converted by 25-hydroxylase in the liver to 25-hydroxyvitamin D [25(OH)D], which is further converted by the 25-hydroxyvitamin D-1α-hydroxylase in the kidneys to the active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D binds to its nuclear vitamin D receptor to exert its physiologic functions. These functions include: promotion of intestinal calcium and phosphate absorption, renal tubular calcium reabsorption, and calcium mobilization from bone. The Endocrine Society's Clinical Practice Guideline defines vitamin D deficiency, insufficiency, and sufficiency as serum concentrations of 25(OH)D of <20 ng/mL, 21-29 ng/mL, and 30-100 ng/mL, respectively. Vitamin D deficiency is a major global public health problem in all age groups. It is estimated that 1 billion people worldwide have vitamin D deficiency or insufficiency. This pandemic of vitamin D deficiency and insufficiency is attributed to a modern lifestyle and environmental factors that restrict sunlight exposure, which is essential for endogenous synthesis of vitamin D in the skin. Vitamin D deficiency is the most common cause of rickets and osteomalacia, and can exacerbate osteoporosis. It is also associated with chronic musculoskeletal pain, muscle weakness, and an increased risk of falling. In addition, several observational studies observed the association between robust levels of serum 25(OH)D in the range of 40-60 ng/mL with decreased mortality and risk of development of several types of chronic diseases. Therefore, vitamin D-deficient patients should be treated with vitamin D2 or vitamin D3 supplementation to achieve an optimal level of serum 25(OH)D. Screening of vitamin D deficiency by measuring serum 25(OH)D is recommended in individuals at risk such as patients with diseases affecting vitamin D metabolism and absorption, osteoporosis, and older adults with a history of falls or nontraumatic fracture. It is important to know if a laboratory assay measures total 25(OH)D or only 25(OH)D3. Using assays that measure only 25(OH)D3 could underestimate total levels of 25(OH)D and may mislead physicians who treat patients with vitamin D2 supplementation.